Table 1.
SIK2-Targeted Therapeutic Strategies in Ovarian Cancer: Clinical Development and Synergistic Efficacy
| Agent Name | Agent Class | Selectivity Profile | Key in vivo Ovarian Cancer Models | Clinical Trial Identifier & Development Status | Synergy & Key Preclinical Findings | References |
|---|---|---|---|---|---|---|
| HG-9-91-01 and derivatives | Pan-SIK ATP-competitive inhibitor | Pan-SIK inhibitor; no direct biochemical IC50 for SIK2 reported, with 90% SIK2 inhibitory activity observed at 5 μM in vitro; off-target activity against SRC, BTK, FGFR1 and other unrelated kinases | No validated in vivo ovarian cancer models for HG-9-91-01 derivatives; only in vitro cell line assays reported for the parent compound HG-9-91-01 | Preclinical development, no trial initiated | Exhibits anti-proliferative activity in ovarian cancer cell lines via SIK2 inhibition; no in vivo antitumor efficacy or synergistic data in ovarian cancer models reported for its derivatives | [63,64] |
| ARN-3236 | SIK2-selective ATP-competitive inhibitor | SIK2-selective (IC50: 20 nM for SIK2, >100-fold selectivity over SIK1/3) | Ovarian cancer subcutaneous CDX model (athymic nude mice); intraperitoneal metastasis model | Preclinical development, no trial initiated | Synergizes with paclitaxel/carboplatin, reverses chemotherapy resistance; suppresses intraperitoneal metastasis | [31,35] |
| ARN-3261 | SIK2-selective ATP-competitive inhibitor | SIK2-selective (IC50: <50 nM for SIK2, >50-fold selectivity over SIK1/3) | Subcutaneous/intraperitoneal CDX models (athymic nude mice); carboplatin-resistant xenograft model | Ongoing Phase I clinical trial (details not yet publicly disclosed) | Circumvents P-glycoprotein-mediated drug efflux; sensitizes 7/8 ovarian cancer cell lines to carboplatin, retains activity in platinum-resistant models | [35,59] |
| MRIA9 | Pan-SIK ATP-competitive inhibitor with optimized kinome-wide selectivity | Pan-SIK activity (cellular IC50: 180 nM for SIK2, 516 nM for SIK1, 127 nM for SIK3); no SIK2 isoform selectivity; exceptional kinome-wide selectivity with inhibitory activity restricted to SIK1-3 and PAK1-3 at 1 μM | No in vivo ovarian cancer CDX/PDX model data reported; only in vitro 3D spheroid model (SKOV3) validation | Preclinical development, no trial initiated | Sensitizes ovarian cancer cells to paclitaxel via disrupting mitotic spindle assembly; inhibits PI3K-AKT signaling to suppress ovarian cancer cell proliferation; minimal off-target kinase activity reduces systemic toxicity risk | [17,70] |
| SIC-19 | First-in-class selective SIK2 protein degrader | Selective SIK2 degradation (DC50: ~0.5 μM for SIK2; no significant SIK1/3 degradation at working concentrations) | Subcutaneous/intraperitoneal CDX models (athymic nude mice); PARP inhibitor-resistant xenograft model | Preclinical development, no trial initiated | Induces durable functional HRD in HRP ovarian cancer; synergizes with olaparib/niraparib to overcome PARP inhibitor resistance | [16] |
| Gel Nap-S+HG | Localized hydrogel delivery system (HG-9-91-01 loaded) | Retains the selectivity profile of parent compound HG-9-91-01 | Ovarian cancer intraperitoneal dissemination model (athymic nude mice) | Preclinical development, no trial initiated | Local sustained drug release; suppresses peritoneal tumor growth with minimal systemic toxicity | [57] |
Abbreviations: SIK, Salt-inducible kinase; IC50, half-maximal inhibitory concentration; CDX, Cell Line-Derived Xenograft; PDX, Patient-derived xenograft; PI3K, phosphoinositide 3-kinase; DC50, half-maximal degradation concentration; PARP, Poly (ADP-ribose) polymerase; HRD, Homologous recombination deficiency; HRP, Homologous recombination-proficient.